title: Cleavage and activation of a Toll-like receptor by microbial proteases.
abstract: Toll-like receptors (TLRs) are innate receptors that show high conservation throughout the animal kingdom. Most TLRs can be clustered into phylogenetic groups that respond to similar types of ligands. One exception is avian TLR15. This receptor does not categorize into one of the existing groups of TLRs and its ligand is still unknown. Here we report that TLR15 is a sensor for secreted virulence-associated fungal and bacterial proteases. Activation of TLR15 involves proteolytic cleavage of the receptor ectodomain and stimulation of NF-κB-dependent gene transcription. Receptor activation can be mimicked by the expression of a truncated TLR15 of which the entire ectodomain is removed, suggesting that receptor cleavage alleviates receptor inhibition by the leucine-rich repeat domain. Our results indicate TLR15 as a unique type of innate immune receptor that combines TLR characteristics with an activation mechanism typical for the evolutionary distinct protease-activated receptors.
authors.affiliation: Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL, Utrecht, The Netherlands.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: de Zoete
authors.forename: Lieneke I
authors.initials: LI
authors.lastname: Bouwman
authors.forename: A Marijke
authors.initials: AM
authors.lastname: Keestra
authors.forename: Jos P M
authors.initials: JP
authors.lastname: van Putten
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D005656:Fungal Proteins / Q000276:immunology* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010447:Peptide Hydrolases / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D005656:Fungal Proteins; D016328:NF-kappa B; D051193:Toll-Like Receptors; D010447:Peptide Hydrolases